NMR relaxation induced by iron oxide particles: testing theoretical models.

Superparamagnetic iron oxide particles find their main application as contrast agents for cellular and molecular magnetic resonance imaging. The contrast they bring is due to the shortening of the transverse relaxation time T 2 of water protons. In order to understand their influence on proton relaxation, different theoretical relaxation models have been developed, each of them presenting a certain validity domain, which depends on the particle characteristics and proton dynamics. The validation of these models is crucial since they allow for predicting the ideal particle characteristics for obtaining the best contrast but also because the fitting of T 1 experimental data by the theory constitutes an interesting tool for the characterization of the nanoparticles. In this work, T 2 of suspensions of iron oxide particles in different solvents and at different temperatures, corresponding to different proton diffusion properties, were measured and were compared to the three main theoretical models (the motional averaging regime, the static dephasing regime, and the partial refocusing model) with good qualitative agreement. However, a real quantitative agreement was not observed, probably because of the complexity of these nanoparticulate systems. The Roch theory, developed in the motional averaging regime (MAR), was also successfully used to fit T 1 nuclear magnetic relaxation dispersion (NMRD) profiles, even outside the MAR validity range, and provided a good estimate of the particle size. On the other hand, the simultaneous fitting of T 1 and T 2 NMRD profiles by the theory was impossible, and this occurrence constitutes a clear limitation of the Roch model. Finally, the theory was shown to satisfactorily fit the deuterium T 1 NMRD profile of superparamagnetic particle suspensions in heavy water.

Bottom-up study of the MRI positive contrast created by the Off-Resonance Saturation sequence.

Superparamagnetic iron oxide nanoparticles (SPM particles) are used in MRI to highlight regions such as tumors through negative contrast. Unfortunately, sources as air bubbles or tissues interfaces also lead to negative contrast, which complicates the image interpretation. New MRI sequences creating positive contrast in the particle surrounding, such as the Off-Resonance Saturation sequence (ORS), have thus been developed. However, a theoretical study of the ORS sequence is still lacking, which hampers the optimization of this sequence. For this reason, this work provides a self-consistent analytical expression able to predict the dependence of the contrast on the sequence parameters and the SPM particles properties. This expression was validated by numerical simulations and experiments on agarose gel phantoms on a 11.7 T scanner system. It provides a fundamental understanding of the mechanisms leading to positive contrast, which could allow the improvement of the sequence for future in vivo applications. The influence of the SPM particle relaxivities, the SPM particle concentration, the echo time and the saturation pulse parameters on the contrast were investigated. The best contrast was achieved with SPM particles possessing the smallest transverse relaxivity, an optimal particle concentration and for low echo times.

Theoretical and experimental study of ON-Resonance Saturation, an MRI sequence for positive contrast with superparamagnetic nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPM particles) are widely used in MRI as negative contrast agents. Their detection is sometimes difficult because negative contrast can be caused by different artifacts. To overcome this problem, MRI protocols achieving positive contrast specific to SPM particles were developed such as the ON-Resonance Saturation (ONRS) sequence. The aim of the present work is to achieve a bottom-up study of the ONRS sequence by an understanding of the physical mechanisms leading to positive contrast. A complete theoretical modeling, a novel numerical simulation approach and experiments on agarose gel phantoms on a 11.7 T MRI system were carried out for this purpose. The influence of the particle properties and concentration - as well as the effect of the sequence parameters on the contrast - were investigated. It was observed that theory and experiments were in strong agreement. The tools developed in this work allowed to predict the parameters leading to the maximum contrast. For example, particles presenting a low transverse relaxivity can provide an interesting positive contrast after optimization of their concentration in the sample.

Phase I - II study to assess the feasibility and activity of the triple combination of 5-fluorouracil/folinic acid, carboplatin and irinotecan (CPT-11) administered by chronomodulated infusion for the treatment of advanced colorectal cancer. Final report of the BE-1603 study.

Thirty-six metastatic colorectal cancer patients received every 2 weeks, as first- (17) or second-line (19) treatment a combined chronotherapy with CPT-11 (infused at day 1 from 2 to 8 a.m.; peak at 5 a.m.), given with 5FU (700 mg/m(2) per day; days 2-5) and folinic acid (300 mg/m(2) per day; days 2-5) both infused from 10 p.m. to 10 a.m. with a peak at 4 a.m., and carboplatin (40 mg/m(2) per day; days 2-5; infused from 10 a.m. to 10 p.m.; peak at 4 p.m.). The doses of CPT11 could be easily pushed from 120 to 180 mg/m(2) in successive cohorts in the phase I part of the study (11 cases). Twenty-five patients were then treated in the phase II of the trial. The overall toxicity was mild leading to dose-reductions in only 11-13% courses. The tumoral activity was interesting with 81% responses and 94% tumour control. Also prolonged survivals were recorded with 8.8 months of progression free and 15.6 months overall survivals. More prolonged survivals were observed in chemotherapy naive patients. Seven patients (19%) could be reoperated from their residual disease.

[Chronotherapy with 5-fluorouracil folinic acid and oxaliplatin delivered over 48 hours every second week in colorectal cancer. The CHC-Liège experience (Belgium)]. / Chronochimiothérapie à base de 5-fluorouracil, acide folinique et oxaliplatine administrée en deux jours toutes les deux semaines pour le cancer colorectal. L'expérience du CHC-Liège (Belgique).

One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)--racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)--palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (>=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty-two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (>=70) experienced worsened survival. In conclusion, we think that our chrono-FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients.

[Chemotherapy for human gastric cancer: a review]. / Qu'attendre de la chimiothérapie dans le cancer de l'estomac en 2008?

The authors review the actual position of medical treatment for human gastric cancer. Chemotherapy has been evaluated first in palliative situation, then as adjuvant post-surgical approach either through systemic or intraperitoneal route. Now chemotherapy may also be proposed as neoadjuvant (before surgery) treatment as part of an integrated global pluridisciplinary approach. New hopes to improve the prognosis come then from both neoadjuvant and adjuvant chemotherapy (+/- radiotherapy) and further from less toxic infusional therapies (chronomodulation), new schedules with proved active molecules (docetaxel, oxaliplatin, irinotecan, pemetrexed) as well as from new targeted treatments (against ie, EGF-receptor and angiogenesis).

[Interest of chronotherapy in multidisciplinary management of oesophageal and gastric cancers]. / Intérêt de la chronothérapie dans le traitement pluridisciplinaire des cancers de l'oesophage et de l'estomac.

The authors evaluated the impact of a chronotherapy with 5-FU, folinic acid and carboplatine (chronomodulated infusions by ambulatory pumps; 5/21 days) for the management of oesophagus (52 cases) and gastric (56 cases) cancer patients. The overall tolerance of treatment was gauged excellent (grade 3-4; % patients: mucitis: 11-23%; leucopenia 6-19%; thrombopenia 18-50%; almost no digestive disturbances nor alopecia). Also tumor outcome was considered interesting with major responses rate in 61% (gastric) to 79% (oesophagus) of patients. The median survival of oesophageal cancer was limited to 9.2 months; the one of disseminated gastric cancer was 12.7 months but 72% of curatively resected patients were alive at 5+ years.

[Chronotherapy combining 5-fluorouracil, folinic acid and carboplatin as first line treatment in metastatic colorectal cancer. A phase 2 study]. / Chronothérapie associant le 5-fluorouracile, l'acide folinique, et le carboplatine en première ligne thérapeutique dans le cancer colorectal métastatique. Une étude de phase 2.

Seventy-two patients suffering from a metastatic colorectal cancer received, as first line treatment, a combination chronotherapy with 5-FU and folinic acid (infused from 10 pm to 10 am with a peak at 4 am, respectively at doses of 700 and 300 mg/m2 per day) and carboplatin (infused at the dose of 40 mg/m2 per day from 10 am to 10 pm with a peak at 4 pm). The courses of four days were repeated every two weeks. A major tumoral response was observed in 60% cases (68% in those not previously treated with adjuvant chemotherapy). The median times to progression and overall survival established at 11 and 27 months. The clinical (grades 3-4 in maximum 5% cases) and hematological (grades 3-4 in maximum 10-29% cases) toxicities were quite limited. Our observations suggest the interest to incorporate carboplatin in the combined infusional treatment of colorectal cancer.

[Feasibility survey (Phase I-II) of a four drugs combination (5-fluorouracil, folinic acid, carboplatin and irinotecan) delivered using a chronomodulated infusion in the treatment of advanced colorectal cancer]. / Etude de faisabilité (Phase I-II) d'une quadruple combinaison associant le 5-fluorouracile, l'acide folinique et le carboplatine à de l'irinotecan administrés en infusion chronomodulée pour le traitement du cancer colorectal avancé.

Seventeen colorectal cancer patients received as first (12 cases) or second line (5 cases) treatment a combined chronotherapy with CPT 11 (infused at day 1 from 2 to 8 am; peak at 5 am), given with 5 FU (700 mg/m2 per day ; days 2-5) and folinic acid (300 mg/m2 per day, days 2-5) both infused from 10 pm to 10 am with a peak at 4 am, and carboplatin (40 mg/m3/day - days 2-5 ; infused from 10 am to 10 pm - peak at 4 pm). The doses of CPT 11 could be easily increased from 120 up to 180 mg/m2 in successive cohorts of four patients through acceptable toxicity. Thus, five patients have already been treated in the phase II part of the trial. An interesting tumoral outcome has been observed: 88% major responses with no progression; median time to progression: nine months and median survival: 19.7 months.

[Adjuvant chemotherapy for Dukes B2 and C colon cancer combining 5-fluorouracil and folinic acid with or without carboplatin. Feasibility and comparison between standard and chronomodulated deliveries]. / Chimiothérapie adjuvante pour le cancer du colon de stades Dukes B2 et C comportant du 5-fluorouracile et de l'acide folinique, avec ou sans carboplatine. Faisabilité et comparaison d'une administration standard à une administration chronomodulée.

Thirty-seven patients operated from a Dukes B2-C colon cancer were randomised to receive as adjuvant infusional chemotherapy, nine 5 FU and folinic acid courses with or without carboplatin, as standard (de Gramont; 2 days every 2 weeks) or chronomodulated administration (4 days every 2 weeks). The overall tolerance was judged excellent with less than 7% courses with dose-adaptations. The two carboplatin arms presented an enhanced haematological toxicity, while some more cutaneous toxicity was observed in the chronomodulated arm with the three drugs.

Sequential administration of epirubicin and paclitaxel for advanced breast cancer. A phase I randomised trial.

Forty-six previously untreated patients with advanced breast cancer were eligible for the present randomised phase I study. It aimed to evaluate the toxicity and activity of a therapeutic sequence with epirubicin on day 1 followed by paclitaxel on day 2 (sequence A) or the reverse sequence, ie., paclitaxel on day 1 followed by epirubicin on day 2 (sequence B). The starting doses of epirubicin and paclitaxel, administered either according to sequence A or B, (level 1 cohort) were 90 mg/m2 and 175 mg/m2, respectively. Per cohort of 3 patients, the dose of paclitaxel was increased by 25 mg/m2 (levels 2 and 4) and of epirubicin by 10 mg/m2 (levels 3 and 5). Treatment was repeated with 3-week intervals. The maximal tolerated dose (MTD) was achieved at level 1 in sequence B (paclitaxel first) and level 3 (epirubicin 100 mg/m2 followed by paclitaxel 200 mg m2) in sequence A. Dose limiting toxicity (DLT) was neutropenia (+/- febrile) in both sequences. Cardiac events occurred in 28% of the patients; significant decrease in left ventricular ejection function (LVEF) was observed in 8/33 and in 2/13 patients in sequence A and B, respectively. This was associated with 5 and 1 cardiac heart failure (CHF), respectively. In 43 evaluable patients, 10 CR and 25 PR were observed (overall response rate 81%). In the 20 patients with locally advanced disease (LABC), the respective numbers were 7 CR and 11 PR; in the 23 metastatic (MBC) patients, 3 CR and 14 PR were recorded. The median survival of the both groups was not reached at 33 + months. In conclusion , the combination of epirubicin and paclitaxel has significant activity in breast cancer. The recommended sequence of both drugs in combination therapy, mainly to avoid neutropenia, is epirubicin day 1 followed by paclitaxel on day 2. Cardiac toxicity remains problematic in either sequence of administration.

[Chronobiological considerations for the management of human head and neck cancer]. / Considérations chronobiologiques pour la prise en charge des tumeurs de la tête et du cou chez l'homme.

The authors reviewed experimental and clinical data (ie, cell kinetics and its circadian control by cyclins, circadian expression of clock genes, chronotolerance to anticancer agents.) justifying to consider the temporal dimension in the medical treatment of human head and neck cancer. A complex infusional chronotherapyschedule (with 5-fluorouracil, folinic acid and carboplatin) was administered to 48 patients. Excellent tolerance and interesting tumour outcome allowed to conclude to an optimised therapeutic index.

[Randomised study to evaluate the chronotolerance of a combination infusional chemotherapy with 5-fluorouracil, folinic acid and carboplatin in non small cell lung cancer (NSCLC) patients]. / Etude randomisée évaluant la chronotolérance d'une association de 5-fluorouracile, acide folinique et carboplatine chez des patients porteurs d'un cancer pulmonaire non à petites cellules (CPNPC).

An infusional ambulatory chronotherapy with 5-FU, folinic acid (FOL) and carboplatin was administered to 45 advanced NSCLC patients. The patients were randomised into 3 groups varying according to the time of administration peak of drugs (reference hours: 4 a.m. for 5 FU (and FOL); 4 p.m. for carboplatin; +/-8 h). The reference schedule appeared best tolerated (regarding hematology and mucositis). This study has prospectively validated the chronotolerance concepts of this complex combination chemotherapy.

[Evaluation of rest-activity rhythms in advanced non-small-cell lung cancer (NSCLC) patients. Importance of corticotherapy?]. / Evaluation des rythmes d'activité et de repos chez des patients porteurs d'un cancer pulmonaire non à petites cellules (CPNPC) de stade avancé. Rôle de la corticothérapie?

The circadian structure (i.e. rest-activity cycle) was evaluated by actometry in a group of 25 advanced NSCLC patients. A better circadian profile was observed in the 6 patients treated with corticosteroïds. However those patients had also a shortened survival.

Human immunodeficiency virus (HIV) type 1 antibodies in perinatal HIV-1 infection: association with human HIV-1 transmission, infection, and disease progression. For the Women and Infants Transmission Study.

Anti -human immunodeficiency virus (HIV) type 1 antibodies in 242 pregnant women and 238 infants were measured at birth and at 1, 2, 4, and 6 months after birth, to estimate their association with perinatal transmission and infant disease progression. Maternal anti-p24 (P=.01) and anti-gp120 (P=.04) antibodies were inversely associated with vertical transmission rates, independent of maternal percentage of CD4 cells, hard drug use, duration of ruptured membranes, serum albumin levels, serum vitamin A levels, and quantitative HIV-1 peripheral mononuclear blood cell culture, but not with maternal plasma immune complex dissociated p24 or HIV-1 RNA copy number, both of which were highly correlated with antibodies. From ages 1-2 months, anti-gp120, -gp41, -p31, and -p66 decayed to a greater extent in infected than in uninfected infants. Infected infants produced anti-p24 antibody by age 2 months, anti-p17 by 4 months, and anti-p41 and anti-gp120 by 6 months. As early as birth, infants with rapid disease progression had lower levels of anti-p24 than did infants whose disease did not rapidly progress, but not independently of HIV-1 RNA levels.

[Chronopharmacologic approach to the administration of anticancer agents in pancreatic adenocarcinoma. Pilot experience]. / Approche chronopharmacologique de l'administration des agents anticancéreux dans l'adénocarcinome pancréatique. Expérience pilote.

The authors first analyzed the potential interest of the delivery of anticancer agents according to chronobiological concepts for human pancreatic cancer. They report their experience on 41 patients treated in adjuvant (12 cases) or palliative (29 cases) situations. The excellent therapeutic index observed warrants further evaluations of this concept in randomized trials.

Chronotherapy with 5-fluorouracil, folinic acid and carboplatin for metastatic colorectal cancer; an interesting therapeutic index in a phase II trial.

The aim of this study was to develop a phase II study gauging the contribution of a daily low-dose of carboplatin combined with 5-fluorouracil (5-FU) and folinic acid (FOL) in a chronotherapy schedule for advanced colorectal cancer patients. 60 patients with metastatic colorectal cancer were included in a phase II trial in which 50% of patients had received prior chemotherapy of up to three regimens. Treatment consisted of a combination of 5-FU (700 mg/m(2)/day) and FOL (300 mg/m(2)/day) infused from 10.00 pm to 10. 00 am peaking at 4.00 am with carboplatin infused from 10.00 am to 10.00 pm at 40 mg/m(2)/day with a peak at 4.00 pm. 4-day courses were repeated every 2 weeks in an ambulatory setting with a programmable pump. Patients experienced excellent tolerance (grades III-IV%): diarrhoea, 8.1; nausea/vomiting, 4.8; mucositis, 3.2; skin or neurological 1.7; granulocytes 29.0; platelets and haemoglobin (Hb) 9.7. Major tumour responses were observed in 47% of cases, 4 complete response (CR), 24 partial response (PR); 3 CR and 6 PR (69%) were recorded in 13 previously untreated patients; 11 (18%) underwent subsequent surgical resection of residual metastases. Median survival was 14.6 months with 22% patients surviving over 2 years (35% survival for responders versus 0 for non-responders). In conclusion, this chronotherapy determined administration of 5-FU/FOL and carboplatin yielded an excellent therapeutic index for the combination and warrants further evaluation in the first-line treatment of metastatic colorectal cancer.

Importance of 5-fluorouracil dose-intensity in a double randomised trial on adjuvant portal and systemic chemotherapy for Dukes B2 and C colorectal cancer.

366 patients fully resected from a Dukes B2 or C colorectal cancer were randomised to receive 6 courses of systemic chemotherapy comprising either 5-fluorouracil (5 FU) alone (arm A: 450 mg/m2/day-5/21 days) or combined folinic acid (FOL) and 5 FU (arm B: respectively 200 mg/m2 racemic form or 100 mg/m2-l-form and 370 mg/m2/day-5/21 days). 173 patients had also been initially randomised to receive one course of intraportal chemotherapy just after surgery or no portal treatment. Oral levamisole (150 mg/day; 3 days every other week) was given to all patients for one year. A significantly higher incidence of leuco-granulocytopenia was observed in the arm A (5 FU alone) inducing more frequent dose delays and adaptations as well as levamisole's withdrawal. Then dose-intensities and dose-intensity products were lower in this arm but the dose intensity expressed in mg/m2/week remained higher (631 +/- 107 vs 557 +/- 99; p < 0.001). The median follow-up in the study was 4.5 years. Relapse free (RFS) and overall survivals (OAS) were prolonged in the 5 FU alone group peculiarly in those patients who had not been randomised for portal treatment. Curves diverged progressively with longer follows-up (at 8 years; RFS in arm A: 67-71% vs 59-53% in arm B; OAS in arm A: 72-74% vs 56-46% in arm B). Patients suffering from a colon or a Dukes C cancer benefited the most from the treatment with 5 FU alone. The results are discussed in the light of other recent adjuvant trials. Well dosed 5 FU over a short period of time without folinic acid may be a valuable and inexpensive adjuvant treatment for colorectal cancer. Levamisole may no longer be recommended in this setting.

Redefining the HIV-infectious window period in the chimpanzee model: evidence to suggest that viral nucleic acid testing can prevent blood-borne transmission.

BACKGROUND: Although it is rare, blood-transmitted HIV infection can occur when a donor presents in the window period between HIV-1 exposure and the first appearance of detectable p24 antigen. STUDY DESIGN AND METHODS: To study this seronegative window period, a chimpanzee (X034) was inoculated with 38 median tissue culture infective doses of HIV-1 IIIB; serum and peripheral blood mononuclear cells were obtained one to two times per week for 12 weeks and then biweekly for 12 weeks. Infectivity was monitored by the detection of serum HIV RNA, cell-associated HIV DNA, p24 antigen, and anti-HIV and by co-culture methods. RESULTS: No HIV markers were noted until 5 weeks after inoculation, at which time virus was isolated and HIV RNA and DNA were detected in plasma and cells, respectively. Anti-HIV and HIV p24 antigen were not present until 8 weeks after inoculation. Plasma and cells obtained from Chimpanzee X034 3 or 4 weeks after exposure were then sequentially inoculated into a second chimpanzee (X176); no HIV infection was observed in this animal during serial follow-up for 24 weeks after each inoculation. In contrast, when the fifth-week HIV-1 RNA- and DNA-positive sample was inoculated, Chimpanzee X176 was unequivocally infected with HIV-1. CONCLUSIONS: Nucleic acid testing narrowed the seronegative window by 3 weeks (37%). More important, there was no demonstrable infectivity in either plasma or peripheral blood mononuclear cells obtained before molecular markers were detectable. This suggests that the infectious window may be considerably shorter than the total window as measured from exposure and that nucleic acid testing might not only shorten the seronegative window, but totally prevent transfusion-transmitted HIV infection.

Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion.

High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.